The research goals of the Section of Molecular Neuroscience are to define the molecular mechanisms underlying the development and function of mammalian chemosensory systems. During the past year, studies aimed at identifying molecules important for gustatory system function were initiated. By examining genome sequences generated by the Human Genome Project, we identified a candidate taste receptor gene, designated T1R3, predicted to encode a novel family 3 G-protein coupled receptor. Based on human sequences, the corresponding mouse T1R3 gene was also cloned and shown to be selectively expressed by taste receptor cells on the tongue. The mouse T1R3 gene was mapped using radiation hybrid mapping to the distal end of chromosome 4 within the genetically defined interval for the Sac locus, a major genetic determinant of sweet preference in mice. Consistent with its candidacy as the Sac locus gene, we demonstrated that the T1R3 genes from taster (Sac +) and non-tasters (Sac -) strains of mice displayed several polymorphisms (resulting in 6 amino acid substitutions). These results, together with expression data, suggest T1R3 may be a sweet receptor and, if so, would be the first mammalian sweet receptor identified. Functional studies to further characterize T1R3 are underway. In an attempt to identify novel genes involved in taste perception, we generated a normalized, subtracted cDNA library from taste tissue. Sequence analysis of 5000 clones from this library indicate that it is highly enriched in taste receptor cell specific genes. In situ hybridization expression studies with several clones has led to the identification of three gene specifically expressed in taste receptor cells. The roles of these gene in taste receptor cell function are being characterized.